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Radiation therapy of intracranial pure germinoma: Result of the German prospective trial MAKEI '83, '86, '89
Brain tumours in children and adults
Wednesday 17 September 1997
(Cn. 40 consecutive patients (pts). bearing T2-T4. NQ-l. MO primary breast cancer received 3 cycles of either epirubicin 120 mglsqm (38 pI) or CMF regimen (2 pis) es neoadjuvant chemotherapy before surgery. All pts were assessed. immediately before and after 3 cycles of CT, for several biological parameters (ER. PgR, KI 67) using immunocytochemistry on fine-needle aspiration biopsy material. Clinical response to treatment was assessed after primary CT; the overall response rate was 24140 piS (60%). The evolution of biomarkers was examined In 39 pts. Ki 67 changed in 11/31 pts (35.5%); EA changed in 16/38 pis (42.1%); PgR changed in 18/39 pts (46.1%) In responder pts EA changed in 27.2%, PgR in 39% and Ki 67 in 41 % whereas non responders showed variations in honnone receptor status in 62"k of pts and in Ki 67 in 28.6% of pts. Primary CT wnh antracycline produces signifICant tumor reduction (60%). At presenl the study is ongoing; non responder piS seem 10 present greater variations in hormone receptor status than responder pts, while a decrease of Ki 67 has been observed In responder pts.
898
PUBLICATION
Tc-99m MISI uptake In advanced breast cancer: Predictive value of response to chemotherapy L. Delgado\, O. Alons02 , I. Alonso\, G. Lag02, Y. Alonzo\' M. Nunez2, G. Sabim 1 , J. Gaudiano2 , I. Muse 1 , E. Touya2 . Department of Clinical
Oncology; 'Nuclear MlKiicine Center; 2 Clinical Hospital of the UnIversIty of Uruguay. Montevideo, Uruguay
Purpose: Multidrug reSistance (MDA) is a major therapeutic problem limiting advanced breast cancer (Be) treatment. Tc·99m MIBI has been reported to be extruded from tumoral cells by the P-glycoprotein (Pgp), encoded by the MOAI gene. The aim 01 this study was to investigate the possible relationship between MIBI uptake and response to chemotherapy in advanced BC. Methods: We stUdied 14 pts with biopsy proven BC; 8 with advanced Iocorregional disease, 3 with Iocorregional and metastalic disease and 3 with recurrent disease. MIBI scintigraphy was performed 2-8 days prior chemotherapy. Images were acqUired 10 minutes and 1 hour post injection 01740 MRq of Tc-99m MIBI. Tumor-ta-normal tissue uptake ratios (TIN) were calCUlated in each evaluable lesion. All pts received combination chemotherapy containing doxorubicin for at least 2 cycles. Results: Twenty-two BC lesions were evaluable for response to chemotherapy. Early TIN were sigmficantly higher in lesions that showed a complete or partial remission than in non responding lesions (1.85, 1.5-2.9 vs. 1.40, 1.3-1.6; median, range respectively; p 0.0006). No lesion with a TIN < 1.5 responded to chemotherapy. Conclusion: These preliminary results suggest that Tc-99m MIBI scintig• raphy may be a valuable tool for gUiding chemotherapy in BC pts.
=
S 199
dose prescription to avoid major adverse effects of Irradiation. The results were Introduced in the current European prosp. study SIOP-CNS-GCT 96 with a further dose reduction to 24 Gy and 16 Gy, resp. to reduce acute and long term side effects.
900
ORAL
Treatment of carcinomatous meningitis (CM) with Intra·CFS sustained-release encapsulated cytarablne (DEPOCYT vs. methotrexate (MTX) N
)
M. Glantz 1 , S. Phupanlch2, K. Jaeckle3 • L. Swinnen', T. Campbell', B. Marias, S. LaFollette7 , M. Chamberlains. DepoCyt Study Group; 'Brown Univ. School. Mad., Providence, RI;2MoffitlCancerCtr. Tampa, FL;3M.D.
Anderson Cancer Clr. Houston, TX; 'Loyola Univ. Chgo, IL; 5 Sharp Healthcare, San Diego, CA; BUnw FL, Gainesville, FL; 'Rush Cancer Inst Chgo, IL; 8 UCSD, San Diego, CA, USA
Neoplastic infiltration 01 the leptomenrnges is a seriious complication of cancer, and current intra-eSF (I-eSF) chemotherapy must be administered by Irequent bolus injections. DepoCyt has an increased half-life in the CSF compared to MTX leading to reduced peak exposure with sustained cy1a• tOXIC CSF levels of ara-G, which allows for markedly decreased frequency of dosing. A randomiZed. Phase III. open-label, multicenter trial of DepoCyt vs. MTX was conducted in patients (pts) with CM. 61 pts were randomized to OepoCyt (31) or MTX (30). Primary neoplasms included breast (22), central nervous system (14), non small eelliung cancer (6), small cell lung cancer (4), melanoma (5), and other (10). PIs received either I-GSF OepoCyt (50 mg ql4d x 2. [Induction); 50 mg q28d x 4 [Consolidation)) or I-GSF MTX (10 mg 2x/Wk x 8 [Induction); 10 mg 1 x/Wk x 8 [Consolidation)). Cytological responses were noted in 9 of 23 (39%) DepoCyt and 7 of 24 (29%) MTX pIs evaluable for response (p 0.34). A Kaplan-Meier estimate of survival betwgen treatment groups (log rank. p O. 12) showed median survival of 105 (DepoCyt) vs. 87 days (MTX); mean survival of 195 (DepoCyt) vs. 128 days (MTX). At 6 months, the number ot surviving pts was 11 (35%) OepoCyt and 5 (17%) MTX pts. I-GSF DepoCyt provides a more conve• nient dosing schedule than MTX, results in a cytological response rate that is at least comparable to MTX. and may offer a survival advantage over conventional I·CSF chemotherapy.
=
=
901
ORAL
Phase II study of Intravenous RMp·7 and carboplatin for chemotherapy naiVe recurrent malignant glioma A. Gregor, M. Lind, C. Osbom. On behaff of the UK RMP·7 Glioma Study
Group; University of Edinburgh, Clinical Oncology, Western General Hospital, UK
Brain tumours in children and adults 899
ORAL
Radiation therapy of Intracranial pure germinoma: Results of the German prospective trials MAKEI '83, '86, '89 A.D. Kortmann 1 , M. Bamberg1 , G. Becker1 , G. CalaminusZ, U. GObeI2, C. Meisner'. 'Department of Radiotherapy. Univ. of Tiiblngen; ~ChI7dren'$
Hospital, Univ. of Dusseldorf; 31nstitute for Medical Information Processing, Un/v. of TUbingen, Germany
Purpose: The trials (MAKEI '831'861'89) were conducted to assess the therapeutic outcome In pure intracranial germinoma after radiolherapy of the neuroaxis alone Ilt reduced radiation doses. Methods: 64 pal. were enrolled. In the MAKEI '831'86 study (n .. 12) the total dose was 36 Gy (neuroaxls) and 14.0 Gy (tumour ene). In the MAKE' '89 study (n .. 51) the dose was reduced to 30 and 15 Gy, resp.. Results: The 5 year relapse-free survival rate was 87.5% +/- 4.8% at a median follow-up of 50 months. The 5 year overall survival rate was 93.0% +1- 3.90/0. 6 to 33 months (mean 16.3 months) atter diagnosis relapses occurred in 6 pat. (9.5%). in 1 pat. a spinal recurrence In 1 pat. cerebral and spinal metastases and in 4 pat. metastases outside the CNS. Salvage chemotherapy achieVed a second complete remiSSion In 5 pal.. 2 pat. died of disease (3.2"10) and 1 pat. (1.6%) of septicemia. Conclusion: Radiotherapy alone is highly effective. Decreased dose lev• els were successful In local tumor control and prevention of spinal seeding. We advocate the Irradiation of the neuroaxix and to continue to reduce the
AMP-7, a selective bradykinin analogue, transiently increases the perme• ability of the blood brain barrier and the delivery of hydrophilic agents into brain tumours. Aim: To assess clinical and 3-0 MAl response to and toxicity of AMP-7 (300 nglkg) + carboplatin (AUC 7) in treatment of recurrent glioma, WHO histology III + IV. Methoda: 45 patients (median age 42, Kamofsky 80%) were treated q 28 days. Neurological Impairment, performance status and steroid use were measured oyer 4 cycles, plus tumour volume by 3-0 MAl at the end of cycles 2 & 4. Clinical response stable or ImproVed compared to baseline. and steroids stable or reduced, for ~2 cycles. Prlmery evaluation of first 4 cycles. Results:
=
ReSponding by Assessment Tool: Intent to Treat Malyal. Orldelll EATl . Improyld/.labla (n • 41) Kamolsky: .tsbll + Improved (n • 45) MRI volume' CRlPR1S[)2 (n. 43)
CA+PR+SD
39122 74
7121/51 79
47120
80 12135130
n
Or.deiV 35/23
70 01112/65 81
1 sn objectlYI, Yehdeted mla.ure of neurologiCal impairment. 2 CR ~ 95% volume reduction + on .terolds; PR > 50% reducflon + liable or reduced steroid.; PO > 50%
Incr. . . ., SO In other sltuallonl: all malnliined ~2 eyde•.
Toxicity: no toxiC deaths, 1 thrornbocytopaenlc withdrawal. Thrombocy• topaenia and/or neutropaenia CTC grades 3/4: 2% at baseline; 27% at cycle 1; 29% at cycle 2; 45% at cycle 3; 35% at cycle 4. 3 patients had treatment-associated transient focal seizures. ConclusIon.: Clinical and MAl response to AMP-7 and csrboplatin combination Is promising and toxicity Is mild.
Wednesday 17 September 1997
(Cn. 40 consecutive patients (pts). bearing T2-T4. NQ-l. MO primary breast cancer received 3 cycles of either epirubicin 120 mglsqm (38 pI) or CMF regimen (2 pis) es neoadjuvant chemotherapy before surgery. All pts were assessed. immediately before and after 3 cycles of CT, for several biological parameters (ER. PgR, KI 67) using immunocytochemistry on fine-needle aspiration biopsy material. Clinical response to treatment was assessed after primary CT; the overall response rate was 24140 piS (60%). The evolution of biomarkers was examined In 39 pts. Ki 67 changed in 11/31 pts (35.5%); EA changed in 16/38 pis (42.1%); PgR changed in 18/39 pts (46.1%) In responder pts EA changed in 27.2%, PgR in 39% and Ki 67 in 41 % whereas non responders showed variations in honnone receptor status in 62"k of pts and in Ki 67 in 28.6% of pts. Primary CT wnh antracycline produces signifICant tumor reduction (60%). At presenl the study is ongoing; non responder piS seem 10 present greater variations in hormone receptor status than responder pts, while a decrease of Ki 67 has been observed In responder pts.
898
PUBLICATION
Tc-99m MISI uptake In advanced breast cancer: Predictive value of response to chemotherapy L. Delgado\, O. Alons02 , I. Alonso\, G. Lag02, Y. Alonzo\' M. Nunez2, G. Sabim 1 , J. Gaudiano2 , I. Muse 1 , E. Touya2 . Department of Clinical
Oncology; 'Nuclear MlKiicine Center; 2 Clinical Hospital of the UnIversIty of Uruguay. Montevideo, Uruguay
Purpose: Multidrug reSistance (MDA) is a major therapeutic problem limiting advanced breast cancer (Be) treatment. Tc·99m MIBI has been reported to be extruded from tumoral cells by the P-glycoprotein (Pgp), encoded by the MOAI gene. The aim 01 this study was to investigate the possible relationship between MIBI uptake and response to chemotherapy in advanced BC. Methods: We stUdied 14 pts with biopsy proven BC; 8 with advanced Iocorregional disease, 3 with Iocorregional and metastalic disease and 3 with recurrent disease. MIBI scintigraphy was performed 2-8 days prior chemotherapy. Images were acqUired 10 minutes and 1 hour post injection 01740 MRq of Tc-99m MIBI. Tumor-ta-normal tissue uptake ratios (TIN) were calCUlated in each evaluable lesion. All pts received combination chemotherapy containing doxorubicin for at least 2 cycles. Results: Twenty-two BC lesions were evaluable for response to chemotherapy. Early TIN were sigmficantly higher in lesions that showed a complete or partial remission than in non responding lesions (1.85, 1.5-2.9 vs. 1.40, 1.3-1.6; median, range respectively; p 0.0006). No lesion with a TIN < 1.5 responded to chemotherapy. Conclusion: These preliminary results suggest that Tc-99m MIBI scintig• raphy may be a valuable tool for gUiding chemotherapy in BC pts.
=
S 199
dose prescription to avoid major adverse effects of Irradiation. The results were Introduced in the current European prosp. study SIOP-CNS-GCT 96 with a further dose reduction to 24 Gy and 16 Gy, resp. to reduce acute and long term side effects.
900
ORAL
Treatment of carcinomatous meningitis (CM) with Intra·CFS sustained-release encapsulated cytarablne (DEPOCYT vs. methotrexate (MTX) N
)
M. Glantz 1 , S. Phupanlch2, K. Jaeckle3 • L. Swinnen', T. Campbell', B. Marias, S. LaFollette7 , M. Chamberlains. DepoCyt Study Group; 'Brown Univ. School. Mad., Providence, RI;2MoffitlCancerCtr. Tampa, FL;3M.D.
Anderson Cancer Clr. Houston, TX; 'Loyola Univ. Chgo, IL; 5 Sharp Healthcare, San Diego, CA; BUnw FL, Gainesville, FL; 'Rush Cancer Inst Chgo, IL; 8 UCSD, San Diego, CA, USA
Neoplastic infiltration 01 the leptomenrnges is a seriious complication of cancer, and current intra-eSF (I-eSF) chemotherapy must be administered by Irequent bolus injections. DepoCyt has an increased half-life in the CSF compared to MTX leading to reduced peak exposure with sustained cy1a• tOXIC CSF levels of ara-G, which allows for markedly decreased frequency of dosing. A randomiZed. Phase III. open-label, multicenter trial of DepoCyt vs. MTX was conducted in patients (pts) with CM. 61 pts were randomized to OepoCyt (31) or MTX (30). Primary neoplasms included breast (22), central nervous system (14), non small eelliung cancer (6), small cell lung cancer (4), melanoma (5), and other (10). PIs received either I-GSF OepoCyt (50 mg ql4d x 2. [Induction); 50 mg q28d x 4 [Consolidation)) or I-GSF MTX (10 mg 2x/Wk x 8 [Induction); 10 mg 1 x/Wk x 8 [Consolidation)). Cytological responses were noted in 9 of 23 (39%) DepoCyt and 7 of 24 (29%) MTX pIs evaluable for response (p 0.34). A Kaplan-Meier estimate of survival betwgen treatment groups (log rank. p O. 12) showed median survival of 105 (DepoCyt) vs. 87 days (MTX); mean survival of 195 (DepoCyt) vs. 128 days (MTX). At 6 months, the number ot surviving pts was 11 (35%) OepoCyt and 5 (17%) MTX pts. I-GSF DepoCyt provides a more conve• nient dosing schedule than MTX, results in a cytological response rate that is at least comparable to MTX. and may offer a survival advantage over conventional I·CSF chemotherapy.
=
=
901
ORAL
Phase II study of Intravenous RMp·7 and carboplatin for chemotherapy naiVe recurrent malignant glioma A. Gregor, M. Lind, C. Osbom. On behaff of the UK RMP·7 Glioma Study
Group; University of Edinburgh, Clinical Oncology, Western General Hospital, UK
Brain tumours in children and adults 899
ORAL
Radiation therapy of Intracranial pure germinoma: Results of the German prospective trials MAKEI '83, '86, '89 A.D. Kortmann 1 , M. Bamberg1 , G. Becker1 , G. CalaminusZ, U. GObeI2, C. Meisner'. 'Department of Radiotherapy. Univ. of Tiiblngen; ~ChI7dren'$
Hospital, Univ. of Dusseldorf; 31nstitute for Medical Information Processing, Un/v. of TUbingen, Germany
Purpose: The trials (MAKEI '831'861'89) were conducted to assess the therapeutic outcome In pure intracranial germinoma after radiolherapy of the neuroaxis alone Ilt reduced radiation doses. Methods: 64 pal. were enrolled. In the MAKEI '831'86 study (n .. 12) the total dose was 36 Gy (neuroaxls) and 14.0 Gy (tumour ene). In the MAKE' '89 study (n .. 51) the dose was reduced to 30 and 15 Gy, resp.. Results: The 5 year relapse-free survival rate was 87.5% +/- 4.8% at a median follow-up of 50 months. The 5 year overall survival rate was 93.0% +1- 3.90/0. 6 to 33 months (mean 16.3 months) atter diagnosis relapses occurred in 6 pat. (9.5%). in 1 pat. a spinal recurrence In 1 pat. cerebral and spinal metastases and in 4 pat. metastases outside the CNS. Salvage chemotherapy achieVed a second complete remiSSion In 5 pal.. 2 pat. died of disease (3.2"10) and 1 pat. (1.6%) of septicemia. Conclusion: Radiotherapy alone is highly effective. Decreased dose lev• els were successful In local tumor control and prevention of spinal seeding. We advocate the Irradiation of the neuroaxix and to continue to reduce the
AMP-7, a selective bradykinin analogue, transiently increases the perme• ability of the blood brain barrier and the delivery of hydrophilic agents into brain tumours. Aim: To assess clinical and 3-0 MAl response to and toxicity of AMP-7 (300 nglkg) + carboplatin (AUC 7) in treatment of recurrent glioma, WHO histology III + IV. Methoda: 45 patients (median age 42, Kamofsky 80%) were treated q 28 days. Neurological Impairment, performance status and steroid use were measured oyer 4 cycles, plus tumour volume by 3-0 MAl at the end of cycles 2 & 4. Clinical response stable or ImproVed compared to baseline. and steroids stable or reduced, for ~2 cycles. Prlmery evaluation of first 4 cycles. Results:
=
ReSponding by Assessment Tool: Intent to Treat Malyal. Orldelll EATl . Improyld/.labla (n • 41) Kamolsky: .tsbll + Improved (n • 45) MRI volume' CRlPR1S[)2 (n. 43)
CA+PR+SD
39122 74
7121/51 79
47120
80 12135130
n
Or.deiV 35/23
70 01112/65 81
1 sn objectlYI, Yehdeted mla.ure of neurologiCal impairment. 2 CR ~ 95% volume reduction + on .terolds; PR > 50% reducflon + liable or reduced steroid.; PO > 50%
Incr. . . ., SO In other sltuallonl: all malnliined ~2 eyde•.
Toxicity: no toxiC deaths, 1 thrornbocytopaenlc withdrawal. Thrombocy• topaenia and/or neutropaenia CTC grades 3/4: 2% at baseline; 27% at cycle 1; 29% at cycle 2; 45% at cycle 3; 35% at cycle 4. 3 patients had treatment-associated transient focal seizures. ConclusIon.: Clinical and MAl response to AMP-7 and csrboplatin combination Is promising and toxicity Is mild.